The population of senior Veterans prone to heart failure (HF) is expanding rapidly. Exercise intolerance and dyspnea are common symptoms that detract from independence and quality of life and also predispose to increased mortality and morbidity. Peripheral pathophysiology, particularly involving skeletal muscle (SkMx) and vascular perfusion, likely exacerbates limitations such that HF symptoms and poor outcomes relate to combined effects of central and peripheral mechanisms. While HF therapeutic guidelines emphasize cardiac therapeutic parameters, goals to modify HF SkMx function may provide vital complementary gains. This proposal focuses on benefits of exercise training for HF and evolves from a pilot analysis we began three years ago. Preliminary data show reduced functional capacity (both aerobic and strength) in older HF patients (mean age 6610 yrs) compared to age-matched healthy controls. SkMx expression of certain genes controlling ubiquitin-mediated proteolysis in muscle correspond to the decreased aerobic and strength indices; lean muscle mass also correlates inversely to reduced strength. We now propose to compare four different exercise regimens (i.e., aerobic, strength, combined aerobic-strength, and inspiratory training) to explore how each modality changes function/symptoms in relation to specific peripheral training effects, i.e., exercise effects on SkMx biology (histology, gene expression), peripheral perfusion, and body composition. Male and female (N=200) systolic HF patients (LVEF d40%) aged e50 years will be studied. Patients will be randomized into one of four 12-week, three weekly training regimens. A comprehensive battery of functional assessments (aerobic, strength, and integrated performance), symptoms, and physiological indices (SkMx histology, gene expression, and perfusion, body composition, and serological measures of inflammation, cytokines, and adipokines) will be assessed before and after training. Specific aims are: (1) To assess differences in functional outcomes relative to the different training regimens (aerobic vs. strength vs. aerobic-strength vs. inspiratory). We hypothesize that aerobic-strength will be superior to aerobic or strength alone. We also hypothesize that inspiratory training will match the affects of traditional aerobic-strength as it imparts aerobic and strengthening physiology to the diaphragm. (2) To assess gene expression and SkMx perfusion in relation to the different training regimens. We hypothesize that proteolytic genes (FoxO, Ubiquitin) will be over-expressed in relation to diminished function and that the genes counteracting SkMx proteolysis (IGF-1, PGC-1) will increase in relation to functional gains. Consistently, we will compare how different training regimens modulate gene expression patterns. We hypothesize that exercise modes that directly stimulate SkMx function (strength and inspiratory) will best decrease proteolytic and in- crease anabolic gene expression patterns, and exercise modes that stimulate central cardiac performance and vascular relaxation (aerobic and inspiratory training) will induce relatively greater changes in SkMx perfusion. PUBLIC HEALTH RELEVANCE: Exercise intolerance and dyspnea are common heart failure (HF) symptoms with detrimental prognostic implications. Our pilot work indicates that HF-mediated changes in skeletal muscle gene expression are germane. We now propose to compare the efficacy of 4 therapeutic exercise training regimens (aerobic, strength, combined aerobic-strength, and inspiratory) to improve exercise capacity and symptoms, and to explore changes in skeletal muscle gene patterns and perfusion that likely determine these clinical effects.